The proposed studies will investigate the control of cyclic GMP (cGMP) metabolism in rat rental cortex (C), inner medulla (M) and isolated glomeruli (G), and the possibility that alterations in cGMP of C or G are involved in the modulation of renin release. Previous observations in our laboratory have demonstrated that the maintenance of basal cGMP and increases in cGMP induced by cholinergic stimuli, bradykinin, ionophore A23187 and histamine in C and M are dependent on Ca++ and O2, and likely involve formation of reactive intermediates which stimulate guanylate cyclase (GC). Several observations implicate oxygenation products of arachidonic acid (AA) as potential intermediates, and suggest involvement of calmodulin (XaM) in Ca++ induced release of AA. The proposed studies will investigate the hypothesis that increases in cGMP induced by Ca++ and 02 dependent stimuli involve (a) Ca++ stimulation of Ca++-CaM dependent acyl hydrolase(s) with release of free AA and (b) oxygenation of AA by tge cyclooxygenease (M) or lipoxygenase (C) pathways to products (endoperoxides or hydroperoxides) which activate GC. The oxygenation products of AA and other fatty acids formed in vitro in slices of C or M by Ca++ and Ca++-dependent agonists of cGMP will be characterized and quantitated by high pressure liquid chromatography. Their capacity to stimulate renal GC-cGMP systems will then be examined. Ca++-dependent acyl hydrolase activities of C, M and G will be characterized in subcellular preparations and their dependence on CaM assessed (1) by use of inhibitors of the Ca++-CaM complex and (2) by attempts to separate CaM from enzyme activity and then reconstitute the system. Since AA and A23187 increase renin release and cGMP in C and G, the role of cGMP in control of renin release in C and G will be examined by assessing (a) effects of known stimuli of renin release on cGMP (b) effects of Ca++-dependent and independent stimuli of cGMP on renin release (c) effects of exogenous cGMP on renin release and (d) interactions between cGMP and cAMP in control of renin release. In G, changes in cAMP, cGMP, prostaglandins and renin release will be monitored concurrently.